Efikasi Vaksin Dengue Jurnal Nejm

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Efficacy and Long-Term Safety of a Dengue

Vaccine in Regions of Endemic Disease
S.R. Hadinegoro, J.L. Arredondo‑García, M.R. Capeding, C. Deseda,
T. Chotpitayasunondh, R. Dietze, H.I. Hj Muhammad Ismail, H. Reynales,
K. Limkittikul, D.M. Rivera‑Medina, H.N. Tran, A. Bouckenooghe,
D. Chansinghakul, M. Cortés, K. Fanouillere, R. Forrat, C. Frago, S. Gailhardou,
N. Jackson, F. Noriega, E. Plennevaux, T.A. Wartel, B. Zambrano, and M. Saville,
for the CYD-TDV Dengue Vaccine Working Group*
A BS T R AC T
BACKGROUND
A candidate tetravalent dengue vaccine is being assessed in three clinical trials The authors’ full names, academic de-
involving more than 35,000 children between the ages of 2 and 16 years in Asian– grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
Pacific and Latin American countries. We report the results of long-term follow-up Saville at Sanofi Pasteur, 2 Ave. Pont Pas-
interim analyses and integrated efficacy analyses. teur, 69367 Lyon CEDEX 07, France, or at
melanie.saville@sanofipasteur.com.
METHODS *A complete list of investigators in the
We are assessing the incidence of hospitalization for virologically confirmed den- CYD-TDV Dengue Vaccine Working
Group is provided in the Supplementa-
gue as a surrogate safety end point during follow-up in years 3 to 6 of two phase ry Appendix, available at NEJM.org.
3 trials, CYD14 and CYD15, and a phase 2b trial, CYD23/57. We estimated vaccine
This article was published on July 27,
efficacy using pooled data from the first 25 months of CYD14 and CYD15. 2015, at NEJM.org.
DOI: 10.1056/NEJMoa1506223
RESULTS
Copyright © 2015 Massachusetts Medical Society.
Follow-up data were available for 10,165 of 10,275 participants (99%) in CYD14 and
19,898 of 20,869 participants (95%) in CYD15. Data were available for 3203 of the
4002 participants (80%) in the CYD23 trial included in CYD57. During year 3 in
the CYD14, CYD15, and CYD57 trials combined, hospitalization for virologically
confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and
39 of 11,089 participants in the control group. Pooled relative risks of hospitaliza-
tion for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all
participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years,
and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older. During year
3, hospitalization for severe dengue, as defined by the independent data monitor-
ing committee criteria, occurred in 18 of 22,177 participants in the vaccine group
and 6 of 11,089 participants in the control group. Pooled rates of efficacy for
symptomatic dengue during the first 25 months were 60.3% (95% CI, 55.7 to 64.5)
for all participants, 65.6% (95% CI, 60.7 to 69.9) for those 9 years of age or older,
and 44.6% (95% CI, 31.6 to 55.0) for those younger than 9 years of age.
CONCLUSIONS
Although the unexplained higher incidence of hospitalization for dengue in year 3
among children younger than 9 years of age needs to be carefully monitored during
long-term follow-up, the risk among children 2 to 16 years of age was lower in the
vaccine group than in the control group. (Funded by Sanofi Pasteur; ClinicalTrials
.gov numbers, NCT00842530, NCT01983553, NCT01373281, and NCT01374516.)
n engl j med nejm.org 1
The New England Journal of Medicine
Downloaded from nejm.org on September 7, 2015. For personal use only. No other uses without permission.
Copyright © 2015 Massachusetts Medical Society. All rights reserved.
A
recombinant, live, attenuated, tet- gle-center phase 2b trial (CYD23) in Thailand
ravalent dengue vaccine (CYD-TDV) has that had a study design similar to that of the
been assessed in two phase 3 randomized CYD14 and CYD15 trials to participate in a sepa-
efficacy trials involving more than 31,000 chil- rate study (CYD57) of 4 years of follow-up in which
dren between the ages of 2 and 14 years in the we are assessing safety in a similar way to the way
Asian–Pacific region (CYD14 trial) and between it is being assessed in the two phase 3 trials.4 Here
the ages of 9 and 16 years in Latin America we report the interim analyses of data from the
(CYD15 trial).1,2 The vaccine was administered in long-term safety phase and integrated analyses
three doses: at baseline, at 6 months, and at 12 of data from the efficacy surveillance phase to
months. Vaccine efficacy against virologically con- provide a global view of the clinical profile of the
firmed dengue and safety were assessed during a CYD-TDV dengue vaccine.
25-month efficacy surveillance phase (i.e., until
13 months after the third dose was adminis- Me thods
tered). Reactogenicity and immunogenicity were
also assessed in a subgroup of participants.1,2 Trial Procedures and Oversight
Vaccination significantly reduced the incidence Interim Long-Term Safety Analyses
of virologically confirmed dengue and showed The long-term safety analyses are based on data
acceptable safety and reactogenicity profiles, find- collected during year 3 of two phase 3 trials in five
ings that were consistent with earlier results. Asian–Pacific countries (CYD14) and five Latin
In the ongoing longer-term follow-up (from American countries (CYD15) and during years 3
year 3 to year 6) to assess safety, we are monitor- and 4 of the CYD23 extension study (CYD57) in
ing the incidence of hospitalization for dengue Thailand (Fig. 1). The participants were originally
as a surrogate end point for disease severity in randomly assigned in a 2:1 ratio to the vaccine
order to evaluate a potential predisposition in group or the control group, stratified according
vaccinated persons to increased severity of dis- to age, with a subgroup of participants assigned
ease.3 In addition, we invited the 4002 children to a study of immunogenicity.1,2,4 Representatives
between the ages of 4 and 11 years from a sin- of the sponsor of the trials, Sanofi Pasteur, were
Pooled efficacy analyses Long-term follow-up safety analyses

Active surveillance phase Long-term follow-up phase (single-blind; ongoing)
(observer-blind; terminated)
Active phase 0 6 12 13 24 25
timeline (months)
Injections
Primary pooled
efficacy analysis:
per-protocol
analysis set
Secondary pooled
efficacy analyses:
modified intention-to
treat analysis set
Secondary exploratory pooled efficacy analysis:
intention-to-treat analysis set
Safety analysis: safety analysis set
Overall study
timeline (years)
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6
Figure 1. Overview of the Surveillance Phase and Long-Term Follow-up Phase of the CYD-TDV Candidate Vaccine Trials.
CYD-TDV is a candidate recombinant, live, attenuated, tetravalent dengue vaccine that has been assessed in two phase 3 randomized
efficacy studies (called CYD14 and CYD15) involving a total of more than 31,000 participants between the ages of 2 and 16 years in
Asian–Pacific and Latin American countries. In addition, 3203 of 4002 participants (80%) who were between the ages of 4 and 11 at ini-
tial enrollment in the phase 2b CYD23 trial in Thailand are being followed in the CYD57 trial. The trials had similar designs. According to
the study designs, the long-term follow-up phase will continue for a total of 6 years after enrollment.
2 n engl j med nejm.org

Efficacy and Safety of a Dengue Vaccine
informed about study-group assignments after and those 9 years of age or older in the CYD14
the analyses for the efficacy surveillance phase and CYD23/57 trials. Ages refer to the ages at
were performed. However, all participants, their initial enrollment.
parents, and staff members at the study sites re-
main unaware of the study-group assignments. Long-Term Follow-up Analyses
Full details regarding the three studies are pro- The objective of the follow-up analyses was to
vided in the study protocol, available with the full describe the long-term safety of the dengue can-
text of this article at NEJM.org. didate vaccine, as recommended by the World
Participants attended yearly clinic visits, with Health Organization (WHO), to verify that the
regular contact (≥1 contact every 3 months by immune response to vaccination does not confer
telephone, text message, or home visit) between a predisposition to severe disease and that the
visits. Hospitalization for acute fever was re- risk of severe disease does not increase with
corded during study contacts and visits, as well time owing to waning titers of vaccine-induced
as by self-report and surveillance at nonstudy antibodies in persons in whom immunity has
hospitals. Blood samples during the acute phase not been naturally boosted. We are assessing the
of illness were obtained for virologic confirma- incidence of hospitalization for virologically con-
tion of dengue infection (see the Methods sec- firmed dengue (of any severity or any serotype)
tion in the Supplementary Appendix, available at for 4 years after the end of the 25-month effi-
NEJM.org). cacy surveillance periods as a surrogate outcome
for severe disease. (For details, see the Methods
Pooled Efficacy Analyses section in the Supplementary Appendix.) In ad-
In the pooled efficacy analyses, we evaluated dition, among the hospitalized participants, we
data from the 25-month efficacy surveillance are assessing the occurrence of severe dengue
phase in the CYD14 and CYD15 trials (Fig. 1).1,2 using the criteria of the independent data moni-
The study designs, objectives, vaccine formula- toring committee and the 1997 WHO criteria for
tion and schedules, hypotheses, and end points dengue hemorrhagic fever. We are recording
were identical in the two trials. Sample sizes clinical signs and symptoms of the hospitalized
differed to account for local incidence data. participants to describe the disease profile and
are collecting data regarding serious adverse events
Trial Oversight that occur during the 4-year safety follow-up.
The sponsor designed the trials and performed
sample testing and data analyses. The investiga- Pooled Efficacy Analyses
tors collected the data, and the sponsor and the The objective of the pooled CYD14 and CYD15
investigators interpreted the data and collabo- analyses was to assess the efficacy of CYD-TDV
rated in the preparation of the manuscript. Rep- against virologically confirmed dengue, hospi-
resentatives of the sponsor had complete access talization for dengue, and severe illness (defined
to the trial data and vouch for the completeness according to the criteria of the independent data
and accuracy of the data and the analyses. The monitoring committee and the WHO criteria for
nonsponsor authors had access to the statistical dengue hemorrhagic fever) associated with any
analyses but not to participant-level data, so that serotype. We repeated the analyses according to
blinding in the ongoing trials could be main- age and, in participants in the immunogenicity
tained. The first draft of the manuscript was subgroups, according to baseline dengue se-
written by a medical writer who was employed rostatus.
by MediCom Consult and was paid by the spon-
sor. All the authors provided critical input in the Data Sets Included in Analyses
preparation of the manuscript and approved the For the interim analysis of long-term follow-up,
submitted version. the safety analysis set included participants who
had received at least one dose of vaccine; par-
Study Outcomes ticipants were analyzed in the group correspond-
All analyses that are presented here were pre- ing to the first injection received, regardless of
specified, except for post hoc analyses of data group assignment. For the pooled efficacy analy-
from participants younger than 9 years of age sis of the primary outcome (i.e., symptomatic,
virologically confirmed dengue of any severity or enrolled in the extension trial, CYD57 (2131 in
any serotype), the analysis was performed in the the vaccine group and 1072 in the control group).
per-protocol efficacy population, which included A total of 10,165 of 10,275 participants (99%) in
participants who had received three doses of the CYD14 trial and 19,898 of 20,869 partici-
vaccine and who had no prespecified protocol pants (95%) in the CYD15 trial who were be-
deviations. For all other outcomes, the analyses tween the ages of 2 and 16 years are being fol-
were performed in the intention-to-treat efficacy lowed (6778 in the vaccine group and 3387 in the
population, which included all participants who control group in the CYD14 trial and 13,268 and
had received at least one injection and who were 6630, respectively, in the CYD15 trial). The vac-
evaluated in the group to which they had been cine and control groups were well balanced with
randomly assigned, regardless of per-protocol respect to age and sex (Table S1 in the Supple-
criteria (see the Methods section in the Supple- mentary Appendix). More participants in the
mentary Appendix). CYD15 trial than in the CYD14 trial were sero-
positive for dengue at baseline, although the num-
Statistical Analysis bers were similar among those who were 9 years
We calculated annual incidence rates and 95% of age or older (Fig. S1 in the Supplementary
confidence intervals for hospitalization for viro- Appendix).
logically confirmed dengue and for severe dis-
ease (as defined according to the criteria of the Interim Long-Term Safety Analyses
independent data monitoring committee and the All Participants
WHO criteria for dengue hemorrhagic fever) for During year 3, the annual incidence of hospital-
any and for all serotypes, for all participants, ization for virologically confirmed dengue was
and according to age group at enrollment. We 0.4% (27 of 6778 participants) in the vaccine group
calculated incidence rates (expressed as percent- and 0.4% (13 of 3387) in the control group in the
ages) as the number of participants who had at CYD14 trial, 0.1% (16 of 13,268 participants) in
least one event divided by the number of partici- the vaccine group and 0.2% (15 of 6630) in the
pants present at the start of the study period. control group in the CYD15 trial, and 1.1% (22 of
Since data were collected for 11 months during 2131 participants) in the vaccine group and 1.1%
year 3 (from month 25 to month 36), the annual (11 of 1072) in the control group in the CYD57
incidence was calculated as the number of cases trial (Table 1). The relative risk of hospitalization
divided by the total number of participants di- for virologically confirmed dengue in the vac-
vided by 11 and multiplied by 12. We calculated cine group as compared with the control group
relative risk as the annual incidence rate ratios was 1.04 (95% confidence interval [CI], 0.52 to
in the vaccine and control groups.1,2 2.19) in the CYD14 trial, 0.53 (95% CI, 0.25 to
The statistical methods that were used for the 1.16) in the CYD15 trial, and 1.01 (95% CI, 0.47
calculations of estimates of vaccine efficacy have to 2.30) in the CYD23/57 trial (Table 1). The
been reported previously.1,2 We used a Cox re- pooled relative risk for the three trials was 0.84
gression model to estimate pooled vaccine effi- (95% CI, 0.56 to 1.24). The majority of patients
cacy, with vaccine group and trial included as had serotype 1 or 2 infection; serotype 4 was the
fixed effects. An analysis of interaction was least frequently identified serotype (Table 1).
added in the model to test for heterogeneity, The length of hospitalization, duration of fe-
with a P value of less than 0.10 considered to ver, and clinical symptoms were similar in the
indicate statistical significance. Suspected inter- three trials (Tables S2A, S2B, and S2C in the
actions were assessed for their clinical and sta- Supplementary Appendix). No clinically impor-
tistical relevance.5 tant differences in the frequencies of signs and
symptoms were observed between the vaccine
and control groups, suggesting that there were
R e sult s
no vaccine-related changes in the clinical picture
Study Participants of hospitalized participants. Similar levels of vire-
A total of 3203 of the 4002 participants (80%) mia were observed among hospitalized partici-
in the CYD23 trial who were between the ages pants in the vaccine group and the control group
of 4 and 11 years at enrollment were subsequently (Table S3 in the Supplementary Appendix).

Table 1. Annual Incidence of Hospitalization for Virologically Confirmed Dengue, According to Trial, Age Group, and Study Period.*
Trial, Age Group, Relative Risk

and Study Period Vaccine Group Control Group (95% CI)
Cases of Total Annual Incidence Cases of Total Annual Incidence

Dengue Participants† Rate‡ Dengue Participants† Rate‡
no. % (95% CI) no. % (95% CI)

CYD14
All participants§ 27 6,778 0.4 (0.3–0.6) 13 3387 0.4 (0.2–0.7) 1.04 (0.52–2.19)
2–5 yr 15 1,636 1.0 (0.6–1.6) 1 813 0.1 (0.0–0.7) 7.45 (1.15–313.80)
6–11 yr 10 3,598 0.3 (0.1–0.6) 8 1806 0.5 (0.2–1.0) 0.63 (0.22–1.83)
12–14 yr 2 1,544 0.1 (0.0; 0.5) 4 768 0.6 (0.2–1.4) 0.25 (0.02–1.74)
<9 yr 19 3,493 0.6 (0.4–0.9) 6 1741 0.4 (0.1–0.8) 1.58 (0.61–4.83)
≥9 yr 8 3,285 0.3 (0.1–0.5) 7 1646 0.5 (0.2–1.0) 0.57 (0.18–1.86)
CYD15
All participants¶ 16 13,268 0.1 (0.1–0.2) 15 6630 0.2 (0.1–0.4) 0.53 (0.25–1.16)
9–11 yr 10 6,029 0.2 (0.1–0.3) 9 3005 0.3 (0.1–0.6) 0.55 (0.20–1.54)
12–16 yr 6 7,239 <0.1 (0.0–0.2) 6 3625 0.2 (0.1–0.4) 0.50 (0.13–1.87)
CYD57
All participants
Year 3‖ 22 2,131 1.1 (0.7–1.7) 11 1072 1.1 (0.6–2.0) 1.01 (0.47–2.30)
Year 4‖ 16 2,131 0.8 (0.4–1.2) 17 1072 1.6 (0.9–2.5) 0.47 (0.22–1.00)
4 or 5 yr
Year 3 5 393 1.4 (0.5–3.2) 1 192 0.6 (0.0–3.1) 2.44 (0.27–115.54)
Year 4 5 393 1.3 (0.4–2.9) 3 192 1.6 (0.3–4.5) 0.81 (0.16–5.24)
6–11 yr
Year 3 17 1,738 1.1 (0.6–1.7) 10 880 1.2 (0.6–2.3) 0.86 (0.37–2.10)
Year 4 11 1,738 0.6 (0.3–1.1) 14 880 1.6 (0.9–2.7) 0.40 (0.16–0.94)
<9 yr
Year 3 19 1,338 1.5 (0.9–2.4) 6 665 1.0 (0.4–2.1) 1.57 (0.60–4.80)
Year 4 13 1,338 1.0 (0.5–1.7) 12 665 1.8 (0.9–3.1) 0.54 (0.23–1.29)
≥9 yr
Year 3 3 793 0.4 (0.1–1.2) 5 407 1.3 (0.4–3.1) 0.31 (0.05–1.58)
Year 4 3 793 0.4 (0.1–1.1) 5 407 1.2 (0.4–2.8) 0.31 (0.05–1.58)
* CYD14 and CYD15 are two phase 3 randomized efficacy studies involving a total of more than 31,000 participants between the ages of 2
and 16 years in Asian–Pacific and Latin American countries, respectively. In addition, 3203 of 4002 participants (80%) who were between
the ages of 4 and 11 at initial enrollment in the phase 2b CYD23 trial in Thailand are being followed in the CYD57 trial. The trials had similar
designs. Listed are virologically confirmed cases of any serotype of dengue during year 3 in the CYD14 and CYD15 trials and in years 3 and
4 in the CYD57 trial.
† Listed is the number of participants at the beginning of each year or the mean number of participants who were followed during the years
included in the period.
‡ Since data were collected for 11 months during year 3 (from month 25 to month 36), the annual incidence was calculated as the number of
cases divided by the total number of participants divided by 11 times 12.
§ During year 3 in the CYD14 trial, the numbers of participants with disease caused by each serotype at baseline in the vaccine group versus
the control group (with patients randomly assigned in a 2:1 ratio) were as follows: serotype 1, 11 vs. 1; serotype 2, 3 vs. 0; serotype 3, 13 vs.
7; and serotype 4, 0 vs. 5.
¶ During year 3 in the CYD15 trial, the numbers of participants with disease caused by each serotype at baseline in the vaccine group versus
the control group were as follows: serotype 1, 5 vs. 5; serotype 2, 8 vs. 11; serotype 3, 3 vs. 0; and serotype 4, 0 vs. 0.
‖ During years 3 and 4 in the CYD57 trial, the numbers of participants with disease caused by each serotype at baseline in the vaccine group
versus the control group were as follows: year 3: serotype 1, 5 vs. 5; serotype 2, 17 vs. 4; serotype 3, 1 vs. 1; and serotype 4, 0 vs. 0; year 4:
serotype 1, 4 vs. 3; serotype 2, 4 vs. 6; serotype 3, 6 vs. 3; and serotype 4, 2 vs. 4.
Overall, during year 3, severe dengue, defined among those who were 9 years of age or older
according to the criteria of the independent data was 0.57 (95% CI, 0.18 to 1.86) in the CYD14
monitoring committee, was reported in 18 of trial and 0.31 (95% CI, 0.05 to 1.58) in the
22,177 participants in the vaccine group and in CYD23/57 trial, findings that were similar to the
6 of 11,089 in the control group (Table S4 in the results in the CYD15 trial, in which all the par-
Supplementary Appendix). In the CYD23/57 trial ticipants were 9 years of age or older (relative
during year 4, severe dengue occurred in 1 par- risk, 0.53; 95% CI, 0.25 to 1.16). The pooled
ticipant in the vaccine group and in 2 partici- relative risk among participants who were 9 years
pants in the control group. All the cases that of age or older was 0.50 (95% CI, 0.29 to 0.86).
were classified as severe according to the criteria An exploratory analysis in the CYD14 trial
of the independent data monitoring committee showed that among participants between the ages
were classified as WHO grade I or II, except for of 9 and 11 years, the relative risk was 1.01 (95%
the cases in 2 participants in the vaccine group CI, 0.22 to 6.23), as compared with a relative risk
during year 3 of the CYD23/57 trial, which were of 0.25 (95% CI, 0.02 to 1.74) among those be-
classified as grade III. All the participants who tween the ages of 12 and 14 years. This trend
were hospitalized for virologically confirmed was not observed in the CYD15 trial (Table 1). In
dengue during follow-up had a full recovery af- year 4 in the CYD57 trial, the relative risk among
ter receiving appropriate supportive treatment. participants who were 9 years of age or older was
similar to that in year 3 (relative risk, 0.31; 95%
Long-Term Follow-up According to Age Group CI, 0.05 to 1.58), whereas the relative risk among
In the CYD14 trial, prespecified age-specific the younger participants had decreased to 0.54
analyses showed a clear trend toward a higher (95% CI, 0.23 to 1.29) (Table 1).
relative risk for hospitalization for virologically In the CYD14 trial, among participants young-
confirmed dengue among younger children, al- er than 9 years of age who were hospitalized for
though the number of cases was low; the relative dengue, severe disease (according to the criteria
risks were 7.45 among children between the ages of the independent data monitoring committee)
of 2 and 5 years, 0.63 among those between the occurred in 8 of 19 participants in the vaccine
ages of 6 and 11 years, and 0.25 among those group and in none of 6 participants in the pla-
between the ages of 12 and 14 years (Table 1). cebo group (relative risk could not be calculated).
The prespecified age-specific analyses in the Among those who were 9 years of age or older,
CYD23/57 trial showed a relative risk of 2.44 severe disease occurred in 3 of 8 participants in
(95% CI, 0.27 to 115.34) among participants the vaccine group and in 1 of 7 participants in the
who were 4 or 5 years of age during year 3 (Ta- control group (relative risk, 1.50; 95% CI, 0.12 to
ble 1). In year 4 of the CYD23/57 trial, the rela- 78.9). The three cases in the vaccine group oc-
tive risk among children who were 4 or 5 years curred in participants who were between the
of age was 0.81, but the upper boundary of the ages of 9 and 11 years at enrollment. In the
95% confidence interval remained more than 1 CYD23/57 trial, all the severe cases occurred in
(95% CI, 0.16 to 5.24). Further analyses in the participants who were younger than 9 years of
CYD15 trial, in which participants between the age. In year 3, the two participants in the vac-
ages of 9 and 16 years were enrolled, showed no cine group in whom the illness was classified as
trend according to age group among those who grade III dengue hemorrhagic fever according to
were between the ages of 9 and 11 years and the WHO criteria had clinical shock.
those who were between the ages of 12 and 16 For year 3, the overall pooled estimate of the
years. relative risk of hospitalization for severe dengue
In year 3, the relative risks among partici- was 1.50 (95% CI, 0.60 to 3.79) for all the par-
pants younger than 9 years of age were similar ticipants, as compared with 0.50 (95% CI, 0.16
in the CYD14 and CYD23/57 trials, with a pooled to 1.55) for participants who were 9 years of age
estimated relative risk of 1.58 (95% CI, 0.83 to or older. Among participants under the age of
3.02), which suggests an overall trend to in- 9 years, there were 12 cases of severe dengue (8 in
creased risk in the vaccine group, although the the CYD14 trial and 4 in the CYD23/57 trial) in
lower boundary of the 95% confidence interval the vaccine group and none in the control group;
was less than 1 (Table 1). The relative risk consequently, the relative risk for this analysis

could not be calculated. The pooled relative risk per-protocol and intention-to-treat analyses in
was driven mainly by the cases occurring in the individual trials and in the pooled analyses
participants younger than 9 years of age. for all outcomes, but multivariate analyses in-
cluding age as a categorical variable (age group)
Hospitalization since Vaccination or as a continuous variable showed significant
Although the relative risk of hospitalization for interaction between age and vaccine group (Fig.
dengue varied in the three studies, within-trial S3 through S6 in the Supplementary Appendix).
estimates showed reductions in risk in the vac- As compared with vaccine efficacies among all
cine group during years 1 and 2 of the efficacy participants, for all outcomes, efficacies were
surveillance phase. With the exception of year 1 higher among participants who were 9 years of
in the CYD23/57 trial, the upper boundaries of age or older and lower among participants who
the 95% confidence intervals were all less than were under 9 years of age. Vaccine efficacies
1 (Table S5 in the Supplementary Appendix). Cu- against dengue in participants who were 9 years
mulative relative risks for hospitalizations that of age or older were similar in the individual
occurred more than 3 years after vaccination were trials, with a pooled estimate of 65.6% (95% CI,
0.46 (95% CI, 0.32 to 0.65) in the CYD14 trial, 60.7 to 69.9) (Fig. 2A), as compared with 44.6%
0.28 (95% CI, 0.18 to 0.44) in the CYD15 trial, (95% CI, 31.6 to 55.0) among participants under
and 0.66 (95% CI, 0.43 to 1.02) in the CYD23/57 the age of 9 years (Fig. 2B).
trial (Table S5 in the Supplementary Appendix). The pooled serotype-specific vaccine effica-
Cumulative relative risks during this period in cies for this outcome ranged from 47.1% (95%
the CYD14 trial were 0.61 (95% CI, 0.39 to 0.95) CI, 31.3 to 59.2) for serotype 2 to 83.2% (95% CI,
among participants younger than 9 years of age 76.2 to 88.2) for serotype 4 among participants
and 0.27 (95% CI, 0.14 to 0.48) among those who were 9 years of age or older (Fig. 2A).
who were 9 years of age or older. A Kaplan– Among those under the age of 9 years, the range
Meier plot showed that there was greater protec- was from 33.6% (95% CI, 1.3 to 55.0) for sero-
tion among participants who were 9 years of age type 2 to 62.1% (95% CI, 28.4 to 80.3) for sero-
or older than among those who were under the type 3 (Fig. 2B).
age of 9 years, and the incidence appeared to be Approximately 80% of the participants 9 years
stable (Fig. S2 in the Supplementary Appendix). of age or older in the immunogenicity subgroup
Cases occurred throughout the follow-up, with in the CYD14 and CYD15 trials were seropositive
similar accrual patterns over time. for dengue at baseline (Fig. S1 in the Supplemen-
The length of hospitalization and duration of tary Appendix). Pooled vaccine efficacy among
fever and clinical symptoms were similar for seropositive participants was 81.9% (95% CI,
those hospitalized during the efficacy surveil- 67.2 to 90.0) among those who were 9 years of
lance phase and the long-term follow-up phase age or older (Fig. 2A), as compared with 70.1%
in all three trials (Tables S2A, S2B, and S2C in (95% CI, 32.3 to 87.3) among those who were
the Supplementary Appendix). No clinically im- younger than 9 years of age (Fig. 2B). In each
portant differences in the frequencies of various study, vaccine efficacies were lower among sero-
signs and symptoms in the hospitalized partici- negative participants who were 9 years of age or
pants were seen between the efficacy surveil- older than among seropositive participants in the
lance phase and the long-term follow-up phase same age group, and the lower boundaries of the
in any of the studies or between the vaccine and 95% confidence intervals were less than 0. How-
control groups, which suggests there were no ever, the pooled vaccine efficacy in this age
changes in the clinical picture of hospitalized group was 52.5%, with a lower boundary of the
cases during long-term follow-up. The levels of 95% confidence interval of more than 0 (Fig. 2A),
viremia were similar to those in the efficacy as compared with a vaccine efficacy of 14.4%
surveillance phase and similar between groups (95% CI, −111.0 to 63.5) among participants
(Table S3 in the Supplementary Appendix). under the age of 9 years (Fig. 2B).
Vaccine efficacies against hospitalization for
Pooled Analyses for Vaccine Efficacy dengue were more than 80% in the individual
Vaccine efficacies for dengue caused by any and trials among participants who were 9 years of
each serotype were generally consistent in the age or older, with a pooled vaccine efficacy of
A Participants 9 Yr of Age or Older

Vaccine Control
Serotype and Trial Group Group Vaccine Efficacy
no. of cases/total no. (95% CI)
All serotypes
CYD14 90/3316 136/1656 67.8 (57.7 to 75.6)
CYD15 277/13,914 385/6940 64.7 (58.7 to 69.8)
CYD14+CYD15 65.6 (60.7 to 69.9)
Serotype 1
CYD14 36/3316 52/1656 65.7 (46.6 to 78.2)
CYD15 99/13,914 109/6940 54.8 (40.2 to 65.9)
CYD14+CYD15 58.4 (47.7 to 66.9)
Serotype 2
CYD14 33/3316 26/1656 36.8 (–10.1 to 63.3)
CYD15 84/13,914 84/6940 50.2 (31.8 to 63.6)
CYD14+CYD15 47.1 (31.3 to 59.2)
Serotype 3
CYD14 11/3316 18/1656 69.5 (31.9 to 87.0)
CYD15 55/13,914 106/6940 74.2 (63.9 to 81.7)
CYD14+CYD15 73.6 (64.4 to 80.4)
Serotype 4
CYD14 10/3316 41/1656 87.9 (75.5 to 94.6)
CYD15 32/13,914 83/6940 80.9 (70.9 to 87.7)
CYD14+CYD15 83.2 (76.2 to 88.2)
Seropositive at baseline
CYD14 7/487 17/251 79.2 (47.2 to 92.7)
CYD15 8/1073 23/512 83.7 (62.2 to 93.7)
CYD14+CYD15 81.9 (67.2 to 90.0)
Seronegative at baseline
CYD14 7/129 8/59 61.6 (–21.1 to 88.1)
CYD15 9/258 9/149 43.2 (–61.6 to 80.0)
CYD14+CYD15 52.5 (5.9 to 76.1)
–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100
Vaccine Efficacy (%)
B Participants under 9 Yr of Age

Vaccine Control Vaccine Efficacy
Serotype in Trial CYD14 Group Group (95% CI)
no. of cases/total no.
All serotypes 196/3532 173/1768 44.6 (31.6 to 55.0)
Serotype 1 80/3532 74/1768 46.6 (25.7 to 61.5)
Serotype 2 64/3532 48/1768 33.6 (1.3 to 55.0)
Serotype 3 19/3532 25/1768 62.1 (28.4 to 80.3)
Serotype 4 30/3532 31/1768 51.7 (17.6 to 71.8)
Seropositive at baseline 11/414 17/193 70.1 (32.3 to 87.3)
Seronegative at baseline 13/295 10/157 14.4 (–111 to 63.5)
–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100


Figure 2 (facing page). Vaccine Efficacy, According to

between year 3 (1.01; 95% CI, 0.47 to 2.30) and
Serotype and Age Group. year 4 (0.47; 95% CI, 0.22 to 1.00) in the
Panel A shows a forest plot indicating vaccine efficacy CYD23/57 trial suggests that results from year 3
against virologically confirmed dengue according to in the CYD14 and CYD15 trials should be inter-
serotype and serostatus at baseline among partici- preted with caution.
pants who were 9 years of age or older at baseline in Hospitalization for dengue was used as an
the CYD14 trial (which enrolled children between the
ages of 2 and 14 years), the CYD15 trial (which en-
end point to minimize the risk of underreport-
rolled children between the ages of 9 and 16 years), ing during long-term follow-up, since partici-
and the meta-analysis of these trials. There was no pants with more severe febrile illness are more
significant interaction between the vaccine group and likely to be hospitalized than are those with
the trial. Panel B shows vaccine efficacy among partic- mild illness. Although hospitalization practices
ipants who were under the age of 9 years in the CYD14
trial.
vary among countries and among health care
centers in the same country, randomization
should have assured a similar likelihood of hos-
80.8% (95% CI, 70.1 to 87.7) (Fig. 3A), as compared pitalization among vaccinated and unvaccinated
with 56.1% (95% CI, 26.2 to 74.1) among partici- participants in each center. Data are limited re-
pants under the age of 9 years (Fig. 3B). Pooled garding markers of dengue severity, and some of
vaccine efficacies for severe dengue, as defined such markers (e.g., plasma leakage) rely on vari-
according to the criteria of the independent data able, imprecise clinical assessment that is de-
monitoring committee, were 93.2% (95% CI, 77.3 pendent on the time since onset. Since the
to 98.0) among participants who were 9 years of methods that were used to capture hospitaliza-
age or older and 44.5 (95% CI, −54.4 to 79.7) tion for dengue in the CYD14 and CYD15 trials
among those under the age of 9 years. The vac- differ between the efficacy surveillance phase
cine efficacies against dengue hemorrhagic fever, and the long-term follow-up phase, the com-
as defined according to the WHO criteria, were parisons of relative risks for the two phases and
92.9% (95% CI, 76.1 to 97.9) and 66.7% (95% CI, the relative risks for the entire studies should be
−4.7 to 90.2) in the two groups, respectively interpreted with caution as well.
(Fig. 3A and 3B). Although there were more hospitalizations
and cases of severe dengue reported among par-
Discussion ticipants under the age of 9 years than among
those older than 9 years of age in the vaccine
The three clinical trials assessing the CYD-TDV group, the clinical pattern of these cases during
candidate vaccine include a 4-year long-term the long-term follow-up safety phase was similar
follow-up safety phase, which was designed in to that reported for hospitalization during the
line with WHO guidelines.6 During year 3 in the efficacy surveillance phase, with no observed
CYD14 trial, 40 participants were hospitalized differences in clinical severity or viremia. In all
for virologically confirmed dengue (27 in the cases, the participants had a complete recovery.
vaccine group and 13 in the control group). In addition, there were no significant differenc-
However, the relative risk in the vaccine group es between cases occurring in the vaccine group
shifted to 1.0, driven by the 15 cases that oc- and the control group among participants under
curred among younger children in the vaccine the age of 9 years. Ongoing safety review during
group, particularly those who were 5 years of long-term follow-up monitors cases between the
age or younger. The combined analysis of the planned interim analyses. Available clinical data
CYD14, CYD15, and CYD57 trials during year 3 are insufficient for drawing definitive conclu-
showed a lower risk of hospitalization for den- sions about the observed imbalance in younger
gue among participants who were 9 years of age children. However, on-site investigations have
or older in the vaccine group than among those shown that major forms of bias (e.g., unblind-
in the control group. This reduction in risk was ing) are unlikely to explain the imbalance.
not observed among children under the age of Several interrelated plausible biologic hypoth-
9 years. However, variability in the relative risks eses could explain the imbalance among the
A Participants 9 Yr of Age or Older

Vaccine Control
Criteria and Trial Group Group Vaccine Efficacy
All severity hospitalized

CYD14 10/3316 27/1656 81.6 (60.7 to 92.0)
CYD15 17/13,914 43/6940 80.3 (64.7 to 89.5)
CYD14+CYD15 80.8 (70.1 to 87.7)
Severe (IDMC) hospitalized
CYD14 2/3316 11/1656 90.9 (58.4 to 99.0)
CYD15 1/13,914 11/6940 95.5 (68.8 to 99.9)
CYD14+CYD15 93.2 (77.3 to 98.0)
DHF (WHO 1997) hospitalized
CYD14 2/3316 11/1656 90.9 (58.4 to 99.0)
CYD15 1/13,914 11/6940 95.5 (64.9 to 99.9)
CYD14+CYD15 92.9 (76.1 to 97.9)
–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100

B Participants under 9 Yr of Age

Vaccine Control
Criteria in CYD14 Trial Group Group Vaccine Efficacy
All severity hospitalized 30/3532 34/1768 56.1 (26.2 to 74.1)
Severe (IDMC) hospitalized 10/3532 9/1768 44.5 (–54.4 to 79.7)
DHF (WHO 1997) hospitalized 6/3532 9/1768 66.7 (–4.7 to 90.2)
–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100

Figure 3. Vaccine Efficacy, According to Group Criteria and Trial.

Panel A shows a forest plot indicating vaccine efficacy among children who were 9 years of age or older at baseline according to rates of
hospitalization for dengue in the intention-to-treat population; rates of severe dengue, as defined according to the criteria of the inde-
pendent data monitoring committee (IDMC); and rates of dengue hemorrhagic fever (DHF), as defined according to the 1997 criteria of
the World Health Organization (WHO). Shown are data for the CYD14 trial (which enrolled children between the ages of 2 and 14 years),
the CYD15 trial (which enrolled children between the ages of 9 and 16), and the meta-analysis of these trials. There was no significant
interaction between the vaccine group and the trial. Panel B shows the same results for children under the age of 9 years in the CYD14
trial.
younger participants. Some of these children densed enrollment period could have clustered
may have had a lower-quality cross-reactive im- these children, as compared with the unvacci-
mune response to vaccination that is prone to nated controls, who would be primed naturally
waning; this may have been the case particularly over a longer period. Further surveillance is re-
among children who were seronegative at the quired to assess whether there is equalization
time of vaccination and therefore more likely to over time. However, if an immune-enhancement
be younger. Subsequent first wild-type infection hypothesis explains our observations, we would
(which is typically less severe) may have occurred have expected elevated clinical viremia and an
in a vaccination-induced immunologic setting, altered cytokine profile, which we did not ob-
which is more analogous to a secondary infec- serve. Age per se may also be important, be-
tion (which is associated with an increased risk cause younger children have less-developed vas-
of severe disease).7 Vaccination during the con- cular physiology and partially immature immune

responses, which could explain the observed included data from the CYD23 trial showed re-
imbalance of events among younger vaccinees in sults similar to those reported here, although
the CYD14 trial during year 3.8-10 Statistical and with higher heterogeneity.
clinical investigations are ongoing to explore In addition to evidence from efficacy trials,
these hypotheses. Since it is essential to con- long-term safety and efficacy data from these stud-
tinue evaluating long-term vaccine efficacy and ies and others (including potential post-authoriza-
safety, the protocols for the CYD14 and CYD15 tion studies of safety and effectiveness) in an inte-
trials were amended to allow for the documenta- grated risk-management plan will provide a more
tion of cases of dengue among both hospitalized complete clinical profile of the CYD-TDV candidate
and nonhospitalized participants as safety and dengue vaccine. Although further follow-up of chil-
efficacy end points during the 4-year long-term dren under the age of 9 years is needed to pro-
follow-up. vide more information regarding the observed
Even though the trials were performed in dif- imbalance, our results show a lower risk of hos-
ferent geographic areas and among different age pitalization for dengue during year 3 among
groups, point estimates of vaccine efficacy were vaccinated children who were 9 years of age or
similar across the trials in the majority of the older than among controls.1,2 The population at
analyses. Pooled vaccine efficacy against dengue risk for dengue varies depending on local epide-
of any severity and any serotype from the effi- miology, with the highest disease burden gener-
cacy surveillance phase among participants who ally observed in age groups representing the
were 9 years of age or older was 65.6%; pooled largest population (i.e., adolescents and adults).11,12
vaccine efficacies for serotype-specific dengue In conclusion, available data from the effica-
were all higher than the nonpooled vaccine ef- cy and long-term follow-up surveillance periods
ficacies. On the basis of a limited number of across three studies in Asian–Pacific and Latin
participants in the immunogenicity subgroups, American tropical and subtropical regions in
pooled analyses of data from participants who which dengue is endemic showed a reduction in
were 9 years of age or older showed that the vac- dengue disease in the efficacy surveillance phase
cine efficacies were 81.9% (95% CI, 67.2 to 90.0) among children who received the vaccine. In ad-
among seropositive participants and 52.5% (95% dition, there was a lower risk of hospitalization
CI, 5.9 to 76.1) among seronegative participants. for dengue overall for up to 2 years after comple-
Data from the CYD23 trial were not included tion of the three-dose vaccination schedule
in the pooled analyses because although the among children between the ages of 9 and 16
CYD23 trial had a similar design to that in the years.
CYD14 and CYD15 trials, there were some no-
Supported by Sanofi Pasteur.
table differences — in particular, the definition Disclosure forms provided by the authors are available with
of acute fever. However, sensitivity analyses that the full text of this article at NEJM.org.
Appendix
The authors’ full names and academic degrees are as follows: Sri Rezeki Hadinegoro, M.D., Ph.D., Jose Luis Arredondo‑García, M.D.,
Maria Rosario Capeding, M.D., Carmen Deseda, M.D., Tawee Chotpitayasunondh, M.D., Reynaldo Dietze, M.D., H.I. Hj Muham-
mad Ismail, M.B., B.S., Humberto Reynales, M.D., Ph.D., Kriengsak Limkittikul, M.D., Doris Maribel Rivera‑Medina, M.D., Huu Ngoc
Tran, M.D., Ph.D., Alain Bouckenooghe, M.D., Danaya Chansinghakul, M.D., Margarita Cortés, M.D., Karen Fanouillere, M.Sc.,
M.P.H., Remi Forrat, M.D., Carina Frago, M.D., Sophia Gailhardou, Pharm.D., Nicholas Jackson, Ph.D., Fernando Noriega, M.D., Eric
Plennevaux, Ph.D., T. Anh Wartel, M.D., Betzana Zambrano, M.D., and Melanie Saville, M.B., B.S., for the CYD-TDV Dengue Vaccine
Working Group
The authors’ affiliations are as follows: Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta (S.R.H.); Instituto Nacional
de Pediatria, Mexico City ( J.L.A.-G.); Research Institute for Tropical Medicine, Muntinlupa City, the Philippines (M.R.C.); Caribbean
Travel Medicine Clinic, San Juan, Puerto Rico (C.D.); Queen Sirikit National Institute of Child Health (T.C.), Faculty of Tropical Medi-
cine, Mahidol University (K.L.), and Sanofi Pasteur (D.C.) — all in Bangkok, Thailand; Nucleo de Doencas Infecciosas, Universidade
Federal do Espirito Santo, Vitoria, ES, Brazil (R.D.); Hospital Kuala Lumpur, Kuala Lumpur, Malaysia (H.I.H.M.I.); Centro de Atencion
e Investigacion Medica SAS–CAIMED (H.R.), and Sanofi Pasteur (M.C.) — both in Bogota, Colombia; Organizacion para el Desarrollo
y la Investigacion Salud en Honduras (ODIS), Tegucigalpa (D.M.R.-M.); Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Viet-
nam (H.N.T.); Sanofi Pasteur, Singapore, Singapore (A.B., C.F., T.A.W.); Sanofi R&D, Chilly-Mazarin (K.F.), Marcy l’Etoile (R.F., E.P.),
and Lyon (S.G., N.J., M.S.) — all in France; Sanofi Pasteur, Swiftwater, PA (F.N.); and Sanofi Pasteur, Montevideo, Uruguay (B.Z.).
References
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healthy children in Asia: a phase 3, ran- .europa.eu/ema/pages/includes/ susceptibility of children to shock? Clin
domised, observer-masked, placebo-con- document/open_document.jsp? Sci (Lond) 2000;98:211-6.
trolled trial. Lancet 2014;384:1358-65. webContentId=WC500003657). 10. Hanna-Wakim R, Yasukawa LL, Sung
2. Villar L, Dayan GH, Arredondo-Gar- 6. Initiative for Vaccine Research, De- P, et al. Age-related increase in the fre-
cía JL, et al. Efficacy of a tetravalent den- partment of Immunization, Vaccines and quency of CD4(+) T cells that produce in-
gue vaccine in children in Latin America. Biologicals. Guidelines for the clinical terferon-gamma in response to staphylo-
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The n e w e ng l a n d j o u r na l of m e dic i n e

Efficacy and Long-Term Safety of a Dengue

Pooled efficacy analyses Long-term follow-up safety analyses

2 n engl j med nejm.org

The New England Journal of Medicine

The New England Journal of Medicine

Trial, Age Group, Relative Risk

Cases of Total Annual Incidence Cases of Total Annual Incidence

no. % (95% CI) no. % (95% CI)

The New England Journal of Medicine

A Participants 9 Yr of Age or Older

B Participants under 9 Yr of Age

Serotype 1 80/3532 74/1768 46.6 (25.7 to 61.5)

Serotype 2 64/3532 48/1768 33.6 (1.3 to 55.0)

Serotype 3 19/3532 25/1768 62.1 (28.4 to 80.3)

Serotype 4 30/3532 31/1768 51.7 (17.6 to 71.8)

Seropositive at baseline 11/414 17/193 70.1 (32.3 to 87.3)

Seronegative at baseline 13/295 10/157 14.4 (–111 to 63.5)

–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100

The New England Journal of Medicine

Figure 2 (facing page). Vaccine Efficacy, According to

A Participants 9 Yr of Age or Older

All severity hospitalized

–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100

B Participants under 9 Yr of Age

Severe (IDMC) hospitalized 10/3532 9/1768 44.5 (–54.4 to 79.7)

DHF (WHO 1997) hospitalized 6/3532 9/1768 66.7 (–4.7 to 90.2)

–30 –20 –10 0 10 20 30 40 50 60 70 80 90 100

Figure 3. Vaccine Efficacy, According to Group Criteria and Trial.

The New England Journal of Medicine

The New England Journal of Medicine

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